The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
Many disease-causing microorganisms possess a neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcos pneumonia, Arthobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
Very recently the first influenza neuraminidase inhibitor, zanamivir, was approved. However, it can only be administered by inhalation. Therefore, there is a continuing need for improved agents for treatment and/or prevention of influenza infection.
Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains. Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus. Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.
The following references disclose substituted cyclopentanes that are useful as neuraminidase inhibitors and treatments for influenza:
Y. Babu, et al., International Patent Application No. WO97/47194, published Dec. 18, 1997; and
Y. Babu, et al., International Patent Application No. WO99/33781, published Jul. 8, 1999.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von ltzstein, et al., European Patent Application No. EP539204, published Apr. 28, 1993 (antiviral agent);
T. Honda, et al., European Patent Application No. EP823428, published Feb. 11, 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. WO98/06712, published Feb. 19, 1998 (sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. WO95/20583, published Aug. 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. WO95/18800, published Jul. 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. WO92/06691, published Apr. 30, 1992 (viral neuraminidase inhibitor);
L. Von Itzstein, et al., U.S. Pat. No. 5,648,379, issued Jul. 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. WO97/32214, published Sep. 4, 1997 (bind to influenza virus neuraminidase active site); and
P. Reece, et al., International Patent Application No. WO98/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility listed after each reference:
Y. Ohira, et al., International Patent Application No. WO98/11083, published Mar. 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721, published Dec. 9, 1998 (antiviral agent); and
B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Pat. No. 5,602,277, issued Feb. 11, 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Pat. No. 5,453,533, issued Sep. 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. WO96/30329, published Oct. 3, 1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Pat. No. 5,763,483, issued Jun. 9, 1998 (neuraminidase inhibitor);
C. Kim, et al., International Patent Application No. WO99/31047, published Jun. 24, 1999 (neuraminidase inhibitor; influenza treatment);
V. Atigadda, et al., J. Med. Chem. 42 2332-2343 (1999) (influenza neuraminidase inhibitor); and
K. Kent, et al., International Patent Application No. 98/07685, published Feb. 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. WO98/17647, published Apr. 30, 1998 discloses piperidine derivatives that are useful as neuraminidase inhibitors.
N. Bischofberger, et al., International Patent Application No. WO96/26933, published Sep. 6, 1996 and N. Bischofberger, et al., International Patent Application No. WO99/14185, published Mar. 25, 1999 disclose various substituted 6-membered ring compounds that are useful as neuraminidase inhibitors.
The following references disclose dihydropyran derivatives that are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. WO97/06157, published Feb. 20, 1997 and U.S. Pat. No. 5,919,819, issued Jul. 6, 1999; and
P. Cherry, et al., International Patent Application No. WO96/36628, published Nov. 21, 1996.
C. Kim, et al., U.S. Pat. No. 5,512,596, issued Apr. 30, 1996 discloses 6-membered aromatic ring derivatives that are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No. WO98/03487, published Jan. 29, 1998 discloses substituted pyridazines that are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No. WO99/06369, published Feb. 11, 1999 discloses piperazine derivatives that are useful as neuraminidase inhibitors.
L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid that are useful as Vibrio cholerae sialidase inhibitors.
W. Brouillette, et al., International Patent Application No. WO99/14191, published Mar. 25, 1999, discloses substituted pyrrolidin-2-one compounds that are useful as neuraminidase inhibitors and treatments for influenza.
The following references disclose siastatin B analogs that are useful as neuraminidase inhibitors:
Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and
Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).
C. Penn, UK Patent Application No. GB2292081, published Feb. 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an influenza vaccine.
An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.
An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.
Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.
Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
In one embodiment, the present invention discloses compounds having Formula Ia, IIa or IIIa 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1 is selected from the group consisting of
(a) xe2x80x94CO2H, (b) xe2x80x94CH2CO2H, (c) xe2x80x94SO3H, (d) xe2x80x94CH2SO3H, (e) xe2x80x94SO2H, (f) xe2x80x94CH2SO2H, (g) xe2x80x94PO3H2, (h) xe2x80x94CH2PO3H2, (i) xe2x80x94PO2H, (j) xe2x80x94CH2PO2H, (k) tetrazolyl, (l) xe2x80x94CH2-tetrazolyl, (m) xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(O)2xe2x80x94R11, (n) xe2x80x94CH2C(xe2x95x90O)xe2x80x94NHxe2x80x94S(O)2xe2x80x94R11, (o) xe2x80x94SO2N(Txe2x80x94R11)R12 and (p) xe2x80x94CH2SO2N(Txe2x80x94R11)R12 
xe2x80x83wherein T is selected from the group consisting of
(i) a bond, (ii) xe2x80x94C(xe2x95x90O)xe2x80x94, (iii) xe2x80x94C(xe2x95x90O)Oxe2x80x94, (iv) xe2x80x94C(xe2x95x90O)Sxe2x80x94, (v) xe2x80x94C(xe2x95x90O)xe2x80x94NR36xe2x80x94, (vi) xe2x80x94C(xe2x95x90S)Oxe2x80x94, (vii) xe2x80x94C(xe2x95x90S)Sxe2x80x94, and (viii) xe2x80x94C(xe2x95x90S)NR36xe2x80x94,
xe2x80x83R11 is selected from the group consisting of
(i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl)alkyl, (v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (viii) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl, (xii) heterocyclic, (xiii) (heterocyclic)alkyl and (xiii) (xiv) (heterocyclic)alkenyl; and
xe2x80x83R12 and R36 are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of
(a) xe2x80x94C(xe2x95x90O)xe2x80x94N(R*)xe2x80x94, (b) xe2x80x94N(R*)xe2x80x94C(xe2x95x90O)xe2x80x94, (c) xe2x80x94C(xe2x95x90S)xe2x80x94N(R*)xe2x80x94, (d) xe2x80x94N(R*)xe2x80x94C(xe2x95x90S)xe2x80x94, (e) xe2x80x94N(R*)xe2x80x94SO2xe2x80x94, and (f)xe2x80x94SO2xe2x80x94N(R*)xe2x80x94 wherein R* is hydrogen, C1-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2xe2x80x94Xxe2x80x94 is 
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are indepedently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or C(R5)2;
R3 and R4 are independently selected from the group consisting of
(a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) xe2x80x94Zxe2x80x94R14 
xe2x80x83wherein Z is
(i) xe2x80x94C(R37a)(R37b)xe2x80x94, (i) C(R47)xe2x95x90C(R48)xe2x80x94, (iii) xe2x80x94Cxe2x89xa1Cxe2x80x94, (iv) xe2x80x94C(xe2x95x90O)xe2x80x94, (v) xe2x80x94C(xe2x95x90S)xe2x80x94, (vi) xe2x80x94C(xe2x95x90NR15)xe2x80x94, (vii) xe2x80x94C(R37a)(OR37c)xe2x80x94, (viii) xe2x80x94C(R 37a)(SR37c)xe2x80x94, (ix) xe2x80x94C(R37a)(N(R37b)(R37c))xe2x80x94, (x) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94, (xi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37c)xe2x80x94, (xii) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)xe2x80x94, (xiii) xe2x80x94C(R37a)(R37b)xe2x80x94N(OH)xe2x80x94, (xiv) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94, (xv) xe2x80x94C(R37a)(R37b)xe2x80x94S(O)xe2x80x94, (xvi) xe2x80x94C(R37a)(R37b)xe2x80x94S(O)2xe2x80x94, (xvii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94, (xviii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)Sxe2x80x94, (xix) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90NR15)xe2x80x94, (xx) xe2x80x94C(R37a)(OR37c)xe2x80x94C(xe2x95x90O)xe2x80x94, (xxi) xe2x80x94C(R37a)(SR37c)xe2x80x94C(xe2x95x90O)xe2x80x94, (xxii) xe2x80x94C(R37a)(OR37c)xe2x80x94C(xe2x95x90S)xe2x80x94, (xxiii) xe2x80x94C(R37a)(SR37c)xe2x80x94C(xe2x95x90S)xe2x80x94, (xxiv) xe2x80x94C(xe2x95x90O)xe2x80x94C(R37a)(OR37c)xe2x80x94, (xxv) xe2x80x94C(O)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxvi) xe2x80x94C(xe2x95x90S)xe2x80x94C(R37a)(OR37c)xe2x80x94, (xvii) xe2x80x94C(xe2x95x90S)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxviii) xe2x80x94C(R37a)(OR37c)xe2x80x94C(R37a)(OR37c)xe2x80x94, (xxix) xe2x80x94C(R37a)(SR37c)xe2x80x94C(R37a)(OR37c)xe2x80x94, (xxx) xe2x80x94C(R37a)(OR37c)xe2x80x94C(xe2x95x90R37a)(SR37c)xe2x80x94, (xxi) xe2x80x94C(R37a)(SR37c)xe2x80x94C(R37a)(SR37c), (xxxii) xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94, (xxxiii) xe2x80x94C(xe2x95x90S)xe2x80x94C(xe2x95x90S)xe2x80x94, (xxxiv) xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (xxxv) xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xxxvi) xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (xxxvii) xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (xxxviii) xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (xxxix) xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xl) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (xli) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (Xlii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (Xliii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xliv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (Xlv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (xlvi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94, (xlvii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94, (xlviii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, (xlix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94, (l) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94, (li) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94, (lii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(O)xe2x80x94N(R37a)xe2x80x94, (liii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (liv) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (lv) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (lvi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (lvii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (lviii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (lix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (lx) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (lxi) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (lxii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (lxiii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (lxiv) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (lxv) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (lxvi) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (lxvii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (lxviii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (lxix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94 or (lxx) xe2x80x94C(R37a)(R37b)xe2x80x94C(R37a)(OR37c)xe2x80x94;
xe2x80x83R14 is
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thiol-substituted alkyl, (vi) R37cO-substituted alkyl, (vii) R37cS-substituted alkyl, (viii) aminoalkyl, (ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl, (xi) R37aOxe2x80x94(Oxe2x95x90)C-substituted alkyl, (xii) R37aSxe2x80x94(Oxe2x95x90)C-substituted alkyl, (xiii) R37aOxe2x80x94(Sxe2x95x90)C-substituted alkyl, (xiv) R37aSxe2x80x94(Sxe2x95x90)C-substituted alkyl, (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl, (xvi) cyanoalkyl, (xvi) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl, (xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl, (xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl, with the proviso that R14 is other than hydrogen when Z is xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94 or xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C (xe2x95x90S)xe2x80x94Sxe2x80x94;
xe2x80x83R37a, R37b, R47, and R48 at each occurrence are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
xe2x80x83R37c at each occurrence is independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl, (xxii) (heterocyclic)alkynyl, (xxiii) xe2x80x94C(xe2x95x90O)xe2x80x94R14, (xxiv) xe2x80x94C(xe2x95x90S)xe2x80x94R14, (xxv) xe2x80x94S(O)2xe2x80x94R14 and (xxvi) hydroxyalkyl;
xe2x80x83or when Z is xe2x80x94C(R37a)(R37b)xe2x80x94N(R37c) then N(R37c) and R14 when taken together are an azido group;
xe2x80x83or when Z is xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c), then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
xe2x80x83or when Z is xe2x80x94C(R37a)(R37b)xe2x80x94, xe2x80x94C(R37a)(OR37cxe2x80x94, xe2x80x94C(R37a)(SR37c) or xe2x80x94C(R37a)(N(R37b)(R37c))xe2x80x94, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring or then OR37c or SR37c or N(R37c) and R14 and the carbon atom to which they are bonded when taken together form a heterocyclic ring containing an O, S or N atom, respectively, and having from 4 to 8 ring atoms;
xe2x80x83R15 is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C1-C12 alkyl, (v) haloalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl, (xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
xe2x80x83R5 at each occurrence is independently selected from the group consisting of
(a) hydrogen, (b) xe2x80x94CH(R38)2, (c) xe2x80x94(CH2)rxe2x80x94Oxe2x80x94R40, (d) C2-C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) xe2x80x94C(xe2x95x90Q1)xe2x80x94R17, and (h) xe2x80x94(CH2)rxe2x80x94N(R19)2 wherein r is 0, 1 or 2; with the proviso that when one R5 is xe2x80x94Oxe2x80x94R40 or xe2x80x94N(R19)2, then the other R5 is other than xe2x80x94Oxe2x80x94R40 or xe2x80x94N(R19)2;
xe2x80x83wherein Q1 is O, S, or N(R18);
xe2x80x83R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
xe2x80x83R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl, (viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl, (xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl, (xv) heterocyclic, (xvi) (heterocyclic)alkyl and (xvii) (heterocyclic)alkenyl;
or one R19 is an N-protecting group;
or the two R5 groups taken together with the carbon atom to which they are bonded, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;
xe2x80x83Y is selected from the group consisting of
(a) C1-C5 alkyl, (b) C1-C5 haloalkyl, (c) C2-C5 alkenyl, (d) C2-C5 haloalkenyl, (e) C2-C5 alkynyl, (f) C3-C5 cycloalkyl, (g) C3-C5 cycloalkyl-C1-to-C3-alkyl, (h) C5 cycloalkenyl, (i) C5 cycloalkenyl-C1-to C3-alkyl, (j) C5 cycloalkenyl C2-to C3-alkenyl, (k) xe2x80x94(CHR39)nOR20, (l) xe2x80x94CH(OR20)xe2x80x94CH2(OR20), (m) xe2x80x94(CHR39)nSR21 (n) phenyl, (o) halo-substituted phenyl, (p) xe2x80x94(CHR39)nC(xe2x95x90Q2)R22, (q) xe2x80x94xe2x80x94(CHR39)nN(xe2x95x90Q3), (r) xe2x80x94N(O)xe2x95x90CHCH3, (s) xe2x80x94(CHR39)nN(CH3)R24 and (t) a heterocyclic ring having from 3 to 6 ring atoms;
xe2x80x83wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42; R20 at each occurrence is independently
(i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl, (v) C1-C3 haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl, (ix) allyl, (x) C2-C3 haloalkenyl, (xi) amino, (xii) xe2x80x94NHCH3, (xiii) xe2x80x94N(CH3)2, (xiv) xe2x80x94NHCH2CH3, (xv) xe2x80x94N(CH3) (CH2CH3), (xvi) xe2x80x94N(CH2CH3)2 or (xvii) xe2x80x94N(xe2x95x90CH2);
xe2x80x83R21 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
xe2x80x83R22 is
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) xe2x80x94N(R28a)(R28b), (xxiii) xe2x80x94CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) xe2x80x94NHNH2, (xxviii) xe2x80x94N(CH3)NH2 or (xxix) xe2x80x94NHNH(CH3);
xe2x80x83R23 and R39 are independently hydrogen or methyl;
xe2x80x83R41 and R42 are independently hydrogen, methyl, or ethyl;
xe2x80x83R24 is selected from the group consisting of
(i) hydrogen, (ii) C1-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) xe2x80x94C(xe2x95x90Q4)xe2x80x94R30, (v) xe2x80x94OR31, and (vi) xe2x80x94N(R32)2, wherein Q4 is O, S, or N(R33);
xe2x80x83R25 is hydroxy, methyl, ethyl, amino, xe2x80x94CN, or xe2x80x94NO2;
xe2x80x83R26 group is hydrogen, methyl or ethyl;
xe2x80x83R28a hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94NHCH3, xe2x80x94N(CH3)2, methoxy, ethoxy, or xe2x80x94CN;
xe2x80x83R28b is hydrogen, methyl or ethyl;
xe2x80x83or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
xe2x80x83R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
xe2x80x83R30 group is hydrogen, methyl, ethyl, xe2x80x94OR34, xe2x80x94SR34, xe2x80x94N(R35)2, xe2x80x94NHOH, xe2x80x94NHNH2, xe2x80x94N(CH3)NH2, or xe2x80x94N(CH2CH3)NH2;
xe2x80x83R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
xe2x80x83R33 group is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94CN, or xe2x80x94NO2;
xe2x80x83R34 group is methyl or ethyl;
xe2x80x83R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2is CHR26 then R22 is selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94C3H7, xe2x80x94OCH3, xe2x80x94SCH3, xe2x80x94Oxe2x80x94C2H5, and xe2x80x94Sxe2x80x94C2H5;
xe2x80x83R6 and R7 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (i) (cycloalkenyl)alkenyl, 0) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (o) (heterocyclic)alkenyl, (p) xe2x80x94OR37a and (q) xe2x80x94N(R37a)2; and
xe2x80x83R8, R9, and R10 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
In another embodiment, the present invention discloses compounds having Formula Ib, IIb or IIIb 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R4, R5, R6, R7, R8, R9, R10, X and Z1 are as defined above for the compounds of the Formula Ia, IIa, and IIIa and wherein
Y is xe2x80x94(CHR39)nN(H)R24 wherein n, R24 and R39 are as defined above for the compounds of the Formula Ia, IIa, and IIIa and wherein
R3 is xe2x80x94Zxe2x80x94R14 
wherein Z is
(i) xe2x80x94C(R37a)(R37b)xe2x80x94, (ii) xe2x80x94C(R37a)(OR37c)xe2x80x94, (iii) xe2x80x94C(R37a)(SR37c)xe2x80x94, (iv) xe2x80x94C(R37a)(N(R37b)(R37c))xe2x80x94, (v) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94, (vi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37c)xe2x80x94, (vii) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)xe2x80x94, (viii) xe2x80x94C(R37a)(R37b)xe2x80x94N(OH)xe2x80x94, (ix) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94, (x) xe2x80x94C(R37a)(R37b)xe2x80x94S(O)xe2x80x94, (xi) xe2x80x94C(R37a)(R37b)xe2x80x94S(O)2xe2x80x94, (xii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94, (xiii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94, (xiv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90NR15), (xv) xe2x80x94C(R37a)(OR37c)xe2x80x94C(xe2x95x90O)xe2x80x94, (xvi) xe2x80x94C(R37a)(SR37c)xe2x80x94C(xe2x95x90O)xe2x80x94, (xvii) xe2x80x94C(R37a)(OR37c)xe2x80x94C(xe2x95x90S)xe2x80x94, (xviii) xe2x80x94C(R37a)(SR37c)xe2x80x94C(xe2x95x90S)xe2x80x94, (xix) xe2x80x94C(R37a)(OR37c)xe2x80x94C(R37a)(OR37c)xe2x80x94, (xx) xe2x80x94C(R37a)(SR37c)xe2x80x94C(R37a)(OR37c)xe2x80x94, (xxi) xe2x80x94C(R37a)(OR37c)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxii) xe2x80x94C(R37a)(SR37c)xe2x80x94C(R37a)(SR37c)xe2x80x94, (xxiii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (xxiv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xxv) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)Oxe2x80x94Oxe2x80x94, (xxvi) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xxvii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (xxviii) xe2x80x94C(R37a)(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (xxix) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94, (xxx) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94, (xxxi) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, (xxxii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94, (xxxiii) xe2x80x94C (R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94, (xxxiv) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94, (xxxv) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (xxxvi) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xxxvii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (xxxviii) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xxxvix) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (xl) xe2x80x94C(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (xli) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (xlii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94N(R37a)xe2x80x94, (xliii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xliv) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94N(R37a)xe2x80x94, (xlv) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (xlvi) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, (xlvii) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xlviii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90O)xe2x80x94Sxe2x80x94, (xiix) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (l) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Oxe2x80x94, (li) xe2x80x94C(R37a)(R37b)xe2x80x94Oxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94, (lii) xe2x80x94C(R37a)(R37b)xe2x80x94Sxe2x80x94C(xe2x95x90S)xe2x80x94Sxe2x80x94 or (iii) xe2x80x94C(R37a)(R37b)xe2x80x94C(R37a)(OR37c)xe2x80x94
wherein R37a, R37b, R37c and R14 are as defined above for the compounds of the Formula Ia, IIa, and IIIa with the proviso that R37a when bonded to the first carbon atom in the Z group is other than hydrogen and with the proviso that R37b when bonded to the first carbon atom in the Z group is other than hydrogen and with the proviso that R14 is other than hydrogen when Z is xe2x80x94C(R37a)(R37b)xe2x80x94, xe2x80x94C(R37a)(OR37c)xe2x80x94, xe2x80x94C(R37a)(SR37c)xe2x80x94 or xe2x80x94C(R37a)(N(R37b)(R37c))xe2x80x94. To illustrate what is meant by first carbon atom in the Z group, representative Z groups are shown in the following list in which the first carbon atom is asterisked: xe2x80x94C*(R37a)(R37b)xe2x80x94, xe2x80x94C*(R37a)(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C*(R37a)(R37b)xe2x80x94N(R37b)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94C*(R37a)(OR37c)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C*(R37a)(R37b)xe2x80x94C(R37a)(OR37c)xe2x80x94.
Preferred compounds of the invention include compounds wherein R3 and R4 are not the same and which have the relative stereochemistry depicted by Formula IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa or IXb: 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R10, X, Y and Z1 are as defined above for Ia, IIa and IIIa for IVa, Va, VIa, VIIa, VIIIa or IXa and wherein R1, R2, R3, R4, R5, R6, R7, R8, R10, X, Y and Z1 are as defined above for Ib, IIb and IIIb for IVb, Vb, VIb, VIIb, VIIIb or IXb.
More preferred compounds of the invention include enantiomerically enriched compounds wherein R3 and R4 are not the same and which have the absolute stereochemistry depicted by Formula Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb: 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R10, X, Y and Z1 are as defined above for Ia, IIa and IIIa for Xa, XIa, XIIa, XIIIa, XIVa, XVa or XVb and wherein R1, R2, R3, R4, R5, R6, R7, R8, R10, X, Y and Z1 are as defined above for Ib, IIb and IIIb for Xb, XIb , XIIb, XIIIb, XIVb or XVb.
Other preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is defined as above;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R3 and R4 are independently selected from hydrogen, heterocyclic and
xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above for compounds having Formula Ia, IIa and IIIa and wherein one of R3 and R4 is other than hydrogen;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen or loweralkyl and
R3 is defined as above for compounds having Formula Ib, IIb and IIIb and wherein one of R3 and R4 is other than hydrogen;
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH(R5)xe2x80x94 wherein R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above; or R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen, fluoro or loweralkyl;
R10 is hydrogen, fluoro or loweralkyl; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3, xe2x80x94N(CH3)R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R24, Q2 and Q3 are defined as above for compounds having Formula Ia, IIa and IIIa;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
More preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is defined as above;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R3 and R4 are independently selected from hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above for compounds having Formula Ia, IIa and IIIa and wherein one of R3 and R4 is other than hydrogen;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIIb, XIIIb, XIVb or XVb, R4 is hydrogen or loweralkyl and
R3 is defined as above for compounds having Formula Ib, IIb and IIIb and wherein one of R3 and R4 is other than hydrogen;
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH(R5)xe2x80x94 wherein R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94CH2)rN(R19)2 wherein r and R19 and R40 are defined as above; or R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above for compounds having Formula Ia, IIa and IIIa;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
Even more preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is defined as above;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C1-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
xe2x80x83alkenyl or xe2x80x94Xxe2x80x94R2 is
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R3 and R4 are independently selected from hydrogen, heterocyclic and
xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above for compounds having Formula Ia, IIa and IIIa and wherein one of R3 and R4 is other than hydrogen;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen or loweralkyl and
R3 is defined as above for compounds having Formula Ib, IIb and IIIb and wherein one of R3 and R4 is other than hydrogen;
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH(R5)xe2x80x94 wherein R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above; or R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
More highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R3 and R4 are independently selected from hydrogen, heterocyclic and
xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above for compounds having Formula Ia, IIa and IIIa and wherein one of R3 and R4 is other than hydrogen;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIIb, XIIIb, XIVb or XVb, R4 is hydrogen or loweralkyl and
R3 is defined as above for compounds having Formula Ib, IIb and IIIb and wherein one of R3 and R4 is other than hydrogen; 
or R5 is hydrogen;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are hydrogen independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
Even more highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R4 is hydrogen or loweralkyl and R3 is heterocyclic or xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as above for compounds having Formula Ia, IIa and IIIa;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen or loweralkyl and
R3 is defined as above for compounds having Formula Ib, IIb and IIIb and wherein one of R3 and R4 is other than hydrogen; 
or R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
Other even more highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) xe2x80x94C(xe2x95x90O)xe2x80x94R14, (h) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 or (i) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)R14 wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
xe2x80x83R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIb, XIVb or XVb, R4 is hydrogen or loweralkyl and
xe2x80x83R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 or xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)R14 wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)xe2x80x94C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
xe2x80x83R37a and R37b are independently selected from the group consisting of (i) loweralkyl and (ii) loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; 
xe2x80x83or R5 is hydrogen;
xe2x80x83R6 and R7 are hydrogen;
xe2x80x83R8 and R9 are hydrogen;
xe2x80x83R10 is hydrogen; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
Most highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)xe2x80x94C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
xe2x80x83R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen and
xe2x80x83R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is (ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)xe2x80x94C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
xe2x80x83R37a is loweralkyl or loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl; 
xe2x80x83or R5 is hydrogen;
xe2x80x83R6 and R7 are hydrogen;
xe2x80x83R8 and R9 are hydrogen;
xe2x80x83R10 is hydrogen; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
Other most highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, lIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
xe2x80x83R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
for compounds having Formula Ib, IIb, IIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen and
xe2x80x83R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
xe2x80x83R37a is loweralkyl or loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl; 
xe2x80x83or R5 is hydrogen;
xe2x80x83R6 and R7 are hydrogen;
xe2x80x83R8 and R9 are hydrogen;
xe2x80x83R10 is hydrogen; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa.
Other most highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R4 is hydrogen and R3 is C(R37a)(OR37c)xe2x80x94R14 
xe2x80x83wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
xe2x80x83R37a is loweralkyl or loweralkenyl; and
xe2x80x83R37c is hydrogen, C1-C3 loweralkyl or allyl;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen and
xe2x80x83R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
xe2x80x83R37a is loweralkyl or loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl; 
xe2x80x83or R5 is hydrogen;
xe2x80x83R6 and R7 are hydrogen;
xe2x80x83R3 and R9 are hydrogen;
xe2x80x83R10 is hydrogen; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NHR24 wherein R24 is hydrogen or xe2x80x94C(xe2x95x90Q4)xe2x80x94R30 wherein Q4 is O, S or N(R33) wherein R33 is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94CN or xe2x80x94NO2 and R30 is xe2x80x94N(R35)2, xe2x80x94NHOH, xe2x80x94NHNH2, xe2x80x94N(CH3)NH2 or xe2x80x94N(CH2CH3)NH2 wherein each R35 is independently hydrogen, methyl or ethyl.
Other most highly preferred compounds of the invention are compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or a salt, ester or prodrug thereof wherein R1 is xe2x80x94CO2H;
xe2x80x94Xxe2x80x94R2 is R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, R4 is hydrogen and R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is
xe2x80x83loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
xe2x80x83R37a is loweralkyl or loweralkenyl; and
xe2x80x83R37c is hydrogen, C1-C3 loweralkyl or allyl;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, R4 is hydrogen and
xe2x80x83R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
xe2x80x83R37a is loweralkyl or loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl; 
xe2x80x83or R5 is hydrogen;
xe2x80x83R5 is hydrogen;
xe2x80x83R6 and R7 are hydrogen;
xe2x80x83R8 and R9 are hydrogen;
xe2x80x83R10 is hydrogen; and
for compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa, Y is C2-C5 alkenyl;
for compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb, Y is xe2x80x94NH2 or xe2x80x94Nxe2x80x94C(xe2x95x90NH)xe2x80x94NH2.
Preferred substituents R1 include xe2x80x94CO2H or esters or prodrugs thereof. Preferred esters include C1-C6 loweralkyl esters, cycloalkyl esters (for example, cyclopropyl ester, cyclohexyl ester and the like), cycloalkylalkyl esters, aryl esters (for example, phenyl ester, 2-methylphenyl ester and the like), arylalkyl esters (for example, benzyl ester, phenylethyl ester and the like), haloalkyl esters (for example, 2,2,2-trichloroethyl ester and the like), heterocyclic esters (for example, N-methylpiperazin-4-yl ester and the like), (heterocyclic)alkyl esters (for example, pyridyl methyl ester, pyridylethyl ester, N-methylpiperazin-4-ylmethyl ester, piperidin-1-ylmethyl ester, morpholin-4-ylmethyl ester, 2-(piperidin-1-yl)ethyl ester, 2-(morpholin-4-yl)ethyl ester, 2. (-N-methylpiperazin-4-yl)ethyl ester, 1,1-dimethyl-2-(piperidin-1-yl)ethyl ester, 1,1-dimethyl-2-(morpholin-4-yl)ethyl ester, 1,1-dimethyl-2-(N-methylpiperazin-4-yl)ethyl ester, phthalidylmethyl ester and the like), di-loweralkylaminoalkyl esters (for example, 2-N,N-dimethylaminoethyl ester, 2-N,N-diethylaminoethyl ester and the like), acyloxyalkyl esters (for example, t-butylcarbonyloxymethyl ester and the like), alkoxycarbonyloxyalkyl esters (for example, t-butyloxycarbonyloxymethyl ester and the like), di-loweralkylaminocarbonylalkyl esters (for example, N,N-dimethylaminocarbonylmethyl ester, N,N-diethylaminocarbonylmethyl ester and the like), acylalkyl esters (for example, t-butylcarbonylmethyl ester and the like), (heterocyclic)carbonylalkyl esters (for example, piperidin-1-ylcarbonylmethyl ester, morpholin-4-ylcarbonylmethyl ester, N-methylpiperazin-4-ylcarbonylmethyl ester and the like), di-loweralkylaminocarbonyloxyalkyl esters (for example, N,N-dimthylaminocarbonyloxymethyl ester, N,N-diethylaminocarbonyloxymethyl ester, N-t-butyl-N-methyl-aminocarbonyloxymethyl ester and the like), alkoxycarbonylalkyl esters (for example, ethoxycarbonylmethyl ester, isopropoxycarbonylmethyl ester and the like), (heterocyclic)carbonyloxyalkyl esters (for example, pyridylcarbonyloxymethyl ester and the like) and the like. Preferred substituents R1 also include xe2x80x94S(O)2NHC(xe2x95x90O)R11 wherein R11 is defined as above.
Most highly preferred substituents R1 include xe2x80x94CO2H or esters or prodrugs thereof. Most highly preferred esters include C1-C6 loweralkyl esters, cycloalkyl esters, cycloalkylalkyl esters or substituted or unsubstituted benzyl esters.
Preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2is 
wherein Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
More preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or xe2x80x94Xxe2x80x94R2 is 
wherein Y1 is xe2x80x94CH2xe2x80x94 and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.
Even more preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl.
More highly preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl.
Even more highly preferred substituents xe2x80x94Xxe2x80x94R2 include R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, R2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, R2xe2x80x94NHxe2x80x94SO2xe2x80x94 or R2xe2x80x94SO2xe2x80x94NHxe2x80x94 wherein R2 is C1-C2 loweralkyl or halo C1-C2 loweralkyl, and especially, CH3xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, CF3xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, CH3xe2x80x94SO2xe2x80x94NHxe2x80x94 or CF3xe2x80x94SO2xe2x80x94NHxe2x80x94.
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH(R5)xe2x80x94 wherein R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above; or R5 is hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 or xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above.
More preferred substituents Z1 are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH(R5)xe2x80x94 wherein R5 is hydrogen, loweralkyl, NH2 or xe2x80x94OH.
More highly preferred substituents Z1 are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94 or 
Even more highly preferred substituents Z1 are xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94 or 
For compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa:
preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as most broadly defined previously herein for Formula Ia, IIa and IIIa and wherein one of R3 and R4 is other than hydrogen;
more highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes heterocyclic or xe2x80x94Zxe2x80x94R14 wherein Z and R14 are defined as most broadly defined previously herein;
even more highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes
(a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) xe2x80x94C(xe2x95x90O)xe2x80x94R14, (h) xe2x80x94C(R37a)(OR37c)xe2x80x94R14 or (i) xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
xe2x80x83R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
xe2x80x83R37c is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl.
Most highly preferred, substituent R4 is hydrogen and R3 includes (a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)xe2x80x94R4 wherein R14 (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
also most highly preferred, substituent R4 is hydrogen and R3 includes (a) heterocyclic, (b) alkyl or (c) xe2x80x94C(R37a)(OR37c)R14 wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl; and
also most highly preferred, substituent R4 is hydrogen and R3 includes xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
R37a is loweralkyl or loweralkenyl; and
R37c is hydrogen, C1-C3 loweralkyl or allyl, and especially, wherein R37c is hydrogen or methyl.
For compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIb, XIVb or XVb:
preferred R4 is hydrogen or loweralkyl and
R3 is defined as above for compounds having Formula Ib, IIb and IIIb and
wherein one of R3 and R4 is other than hydrogen;
more highly preferred R4 is hydrogen or loweralkyl and
R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 or xe2x80x94C(R37a)(R37b)xe2x80x94N(O)(R37c)R14 wherein R14 is (iii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) loweralkyl and (ii) loweralkenyl; and
R37c is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
even more highly preferred R4 is hydrogen and R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is (iv) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)xe2x80x94(Oxe2x95x90)C-substituted alkyl or (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl;
R37a is loweralkyl or loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
most highly preferred R4 is hydrogen and R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is loweralkyl or loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl; and
also most highly preferred R4 is hydrogen and R3 is xe2x80x94C(R37a)(OR37c)xe2x80x94R14 wherein R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;
R37a is loweralkyl or loweralkenyl; and
R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl.
Preferred substituents R5 include those independently selected from hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 and xe2x80x94(CH2)rN(R19)2 wherein r and R19 and R40 are defined as above.
More preferred substituents R5 are independently selected from hydrogen, loweralkyl, xe2x80x94(CH2)rOR40 and xe2x80x94(CH2)rN(R19)2 wherein r is 0 or 1 and one R19 is hydrogen or loweralkyl and the other R19 is hydrogen, loweralkyl or an N-protecting group and R40 is hydrogen.
Even more preferred substituents R5 are independently selected from hydrogen, loweralkyl, xe2x80x94NH2 and xe2x80x94OH.
Most highly preferred, R5 is hydrogen, xe2x80x94NH2 or xe2x80x94OH.
Preferred substituents R6 and R7 include independently hydrogen and loweralkyl. Most highly preferred, R6 and R7 are hydrogen.
Preferred substituents R8, R9 and R10 include independently hydrogen, fluoro and loweralkyl. Most highly preferred, R8, R9 and R10 are hydrogen.
For compounds having Formula Ia, IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa or XVa:
preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3, xe2x80x94N(CH3)R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R24, Q2 and Q3 are defined as above;
more preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl, xe2x80x94C(xe2x95x90Q2)R22, xe2x80x94N(xe2x95x90Q3), xe2x80x94N(O)xe2x95x90CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above;
even more preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y include:
xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHF, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94CHxe2x95x90CHxe2x80x94CF3, xe2x80x94CHxe2x95x90CHCl, xe2x80x94CHxe2x95x90CHBr, xe2x80x94CHxe2x95x90CF2, xe2x80x94CHxe2x95x90CF(CH3), xe2x80x94CHxe2x95x90CF(CF3), xe2x80x94CHxe2x95x90CFCl, xe2x80x94CHxe2x95x90CFBr, xe2x80x94CHxe2x95x90C(CH3)2, xe2x80x94CHxe2x95x90C(CH3) (CF3), xe2x80x94CHxe2x95x90CCl(CH3), xe2x80x94CHxe2x95x90CBr(CH3), xe2x80x94CHxe2x95x90C(CF3)2, xe2x80x94CHxe2x95x90CCl(CF3), xe2x80x94CHxe2x95x90CBr(CF3), xe2x80x94CHxe2x95x90CCl2, xe2x80x94CHxe2x95x90CClBr, xe2x80x94CFxe2x95x90CH2, xe2x80x94CFxe2x95x90CHF, xe2x80x94CFxe2x95x90CHxe2x80x94CH3, xe2x80x94CFxe2x95x90CHxe2x80x94CF3, xe2x80x94CFxe2x95x90CHCl, xe2x80x94CFxe2x95x90CHBr, xe2x80x94CFxe2x95x90CF2, xe2x80x94CFxe2x95x90CF(CH3), xe2x80x94CFxe2x95x90CF(CF3), xe2x80x94CFxe2x95x90CFCl, xe2x80x94CFxe2x95x90CFBr, xe2x80x94CFxe2x95x90C(CH3)2, xe2x80x94CFxe2x95x90C(CH3) (CF3), xe2x80x94CFxe2x95x90CCl(CH3), xe2x80x94CFxe2x95x90CBr(CH3), xe2x80x94CFxe2x95x90C(CF3)2, xe2x80x94CFxe2x95x90CCl(CF3), xe2x80x94CFxe2x95x90CBr(CF3), xe2x80x94CFxe2x95x90CCl2, xe2x80x94CFxe2x95x90CClBr, xe2x80x94C(CH3)xe2x95x90CH2, xe2x80x94C(CH3)xe2x95x90CHF, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH3, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CF3, xe2x80x94C(CH3)xe2x95x90CHCl, xe2x80x94C(CH3)xe2x95x90CHBr, xe2x80x94C(CH3)xe2x95x90CF2, xe2x80x94C(CH3)xe2x95x90CF(CH3), xe2x80x94C(CH3)xe2x95x90CF(CF3), xe2x80x94C(CH3)xe2x95x90CFCl, xe2x80x94C(CH3)xe2x95x90CFBr, xe2x80x94C(CH3)xe2x95x90C(CH3)2, xe2x80x94C(CH3)xe2x95x90C(CH3) (CF3), xe2x80x94C(CH3)xe2x95x90CCl(CH3), xe2x80x94C(CH3)xe2x95x90CBr(CH3), xe2x80x94C(CH3)xe2x95x90C(CF3)2, xe2x80x94C(CH3)xe2x95x90CCl(CF3), xe2x80x94C(CH3)xe2x95x90CBr(CF3), xe2x80x94C(CH3)xe2x95x90CCl2, xe2x80x94C(CH3)xe2x95x90CClBr, xe2x80x94C(CF3)xe2x95x90CH2, xe2x80x94C(CF3)xe2x95x90CHF, xe2x80x94C(CF3)xe2x95x90CHxe2x80x94CH3, xe2x80x94C(CF3)xe2x95x90CHxe2x80x94CF3, xe2x80x94C(CF3)xe2x95x90CHCl, xe2x80x94C(CF3)xe2x95x90CHBr, xe2x80x94C(CF3)xe2x95x90CF2, xe2x80x94C(CF3)xe2x95x90CF(CH3), xe2x80x94C(CF3)xe2x95x90CF(CF3), xe2x80x94C(CF3)xe2x95x90CFCl, xe2x80x94C(CF3)xe2x95x90CFBr, xe2x80x94C(CF3)xe2x95x90C(CH3)2, xe2x80x94C(CF3)xe2x95x90C(CH3)(CF3), xe2x80x94C(CF3)xe2x95x90CCl(CH3), xe2x80x94C(CF3)xe2x95x90CBr(CH3), xe2x80x94C(CF3)xe2x95x90C(CF3)2, xe2x80x94C(CF3)xe2x95x90CCl(CF3), xe2x80x94C(CF3)xe2x95x90CBr(CF3), xe2x80x94C(CF3)xe2x95x90CCl2, xe2x80x94C(CF3)xe2x95x90CClBr, xe2x80x94CClxe2x95x90CH2, xe2x80x94CClxe2x95x90CHF, xe2x80x94CClxe2x95x90CHxe2x80x94CH3, xe2x80x94CClxe2x95x90CHxe2x80x94CF3, xe2x80x94CClxe2x95x90CHCl, xe2x80x94CClxe2x95x90CHBr, xe2x80x94CClxe2x95x90CF2, xe2x80x94CClxe2x95x90CF(CH3), xe2x80x94CClxe2x95x90CF(CF3), xe2x80x94CClxe2x95x90CFCl, xe2x80x94CClxe2x95x90CFBr, xe2x80x94CClxe2x95x90C(CH3)2, xe2x80x94CClxe2x95x90C(CH3) (CF3), xe2x80x94CClxe2x95x90CCl(CH3), xe2x80x94CClxe2x95x90CBr(CH3), xe2x80x94CClxe2x95x90C(CF3)2, xe2x80x94CClxe2x95x90CCl(CF3), xe2x80x94CClxe2x95x90CBr(CF3), xe2x80x94CClxe2x95x90CCl2, xe2x80x94CClxe2x95x90CClBr, xe2x80x94CHxe2x95x90CHxe2x80x94CH2CH3, xe2x80x94CHxe2x95x90CFxe2x80x94CH2CH3, xe2x80x94CFxe2x95x90CHxe2x80x94CH2CH3, xe2x80x94CFxe2x95x90CFxe2x80x94CH2CH3, xe2x80x94CHxe2x95x90C(CH3)(CH2CH3), xe2x80x94CFxe2x95x90C(CH3)(CH2CH3), xe2x80x94CHxe2x95x90CCl(CH2CH3), xe2x80x94CFxe2x95x90CCl(CH2CH3), xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH2CH3, xe2x80x94C(CH3)xe2x95x90CFxe2x80x94CH2CH3, xe2x80x94CClxe2x95x90CHxe2x80x94CH2CH3, xe2x80x94CClxe2x95x90CFxe2x80x94CH2CH3, xe2x80x94C(CH2CH3)xe2x95x90CH2, xe2x80x94C(CH2CH3)xe2x95x90CHF, xe2x80x94C(CH2CH3)xe2x95x90CF2, xe2x80x94C(CH2CH3)xe2x95x90CHxe2x80x94CH3, xe2x80x94C(CH2CH3)xe2x95x90CFxe2x80x94CH3, xe2x80x94C(CH2CH3)xe2x95x90CHxe2x80x94Cl, xe2x80x94C(CH2CH3)xe2x95x90CFCl;
representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinyl, thiadiazolyl, thiadiazolinyl, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl;
more highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl; and
most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, especially, cis-propenyl.
For compounds having Formula Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, VIIIb, IXb, Xb, XIb, XIIb, XIIIb, XIVb or XVb:
preferred Y is xe2x80x94NHR24 wherein R24 is defined as above for compounds having Formula Ia, IIa and IIIa;
more preferred Y is xe2x80x94NHR24 wherein R24 is hydrogen or xe2x80x94C(xe2x95x90Q4)xe2x80x94R30 wherein Q4 is O, S or N(R33) wherein R33 is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94CN or xe2x80x94NO2 and R30 is xe2x80x94N(R35) 2, xe2x80x94NHOH, xe2x80x94NHNH2, xe2x80x94N(CH3)NH2 or xe2x80x94N(CH2CH3)NH2 wherein each R35 is independently hydrogen, methyl or ethyl; and
even more preferred Y is xe2x80x94NH2 or xe2x80x94Nxe2x80x94C(xe2x95x90NH)xe2x80x94NH2.
Preferred definitions for the substituents in the compounds of the invention also apply to the intermediates disclosed herein that are useful in the preparation of the compounds of the invention.
The term xe2x80x9cacid protecting groupxe2x80x9d as used herein refers to groups used to protect acid groups (for example, xe2x80x94CO2H, xe2x80x94SO3H, xe2x80x94SO2H, xe2x80x94PO3H2, xe2x80x94PO2H groups and the like) against undesirable reactions during synthetic procedures. Commonly used acid protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley and Sons, New York (1991), which is incorporated herein by reference. Most frequently, such acid protecting groups are esters.
Such esters include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
arylalkyl esters including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl) (aryl)silyl esters and (loweralkyl) (di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.
Preferred acid protecting groups are loweralkyl esters.
The term xe2x80x9cactivated carboxylic acid groupxe2x80x9d as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,Nxe2x80x2-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
The term xe2x80x9cacylxe2x80x9d as used herein, refers to groups having the formula xe2x80x94C(xe2x95x90O)xe2x80x94R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups as R95 are loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.
The term xe2x80x9cacylalkylxe2x80x9d as used herein refers to an acyl group appended to an alkyl radical. Representative examples of acylalkyl groups include acetylmethyl, acetylethyl, propionylmethyl, propionylethyl and the like.
The term xe2x80x9cacyloxyalkylxe2x80x9d as used herein refers to an acyloxy group (i.e., R95xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R95 is hydrogen or an alkyl group) which is appended to an alkyl radical. Representative examples of acyloxyalkyl include acetyloxymethyl, acetyloxyethyl, propioyloxymethyl, propionyloxyethyl and the like.
The term xe2x80x9cacylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term xe2x80x9clower alkenylxe2x80x9d refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
The term xe2x80x9calkenylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term xe2x80x9clower alkenylenexe2x80x9d refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94OR81 where R81 is an alkenyl group.
The term xe2x80x9calkoxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyl groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94Oxe2x80x94R96xe2x80x94Oxe2x80x94R97 wherein R97 is loweralkyl, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein, refers to groups having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94R80, where R80 is an alkoxy group.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein, refers to groups having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94R79, appended to the parent molecular moiety through an alkylene linkage, where R79 is an alkoxy group.
The term xe2x80x9calkoxycarbonyloxyalkylxe2x80x9d as used herein refers to an alkoxycarbonyloxy group (i.e., R80xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R80 is an alkoxy group) appended to an alkyl radical. Representative examples of alkoxycarbonyloxyalkyl include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term xe2x80x9cloweralkylxe2x80x9d refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl-propyl, n-hexyl, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, xe2x80x94N(R27)xe2x80x94 and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term xe2x80x9calkylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94NHR91 wherein R91 is an alkyl group. Preferred R91 groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
The term xe2x80x9calkylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term xe2x80x9clower alkylenexe2x80x9d refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (xe2x80x94CH2xe2x80x94), 1,2-ethylene (xe2x80x94CH2CH2xe2x80x94), 1,1-ethylene (xe2x80x94CH(CH3)xe2x80x94), 1,3-propylene (xe2x80x94CH2CH2CH2xe2x80x94), 2,2-dimethylpropylene (xe2x80x94CH2C(CH3)2CH2xe2x80x94), and the like. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, xe2x80x94N(R27)xe2x80x94 and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94SO2xe2x80x94R78, where R78 is an alkyl group. Preferred groups R78 are loweralkyl groups.
The term xe2x80x9calkylsulfonylaminoxe2x80x9d as used herein refers to the group having the formula, xe2x80x94SO2xe2x80x94R77, appended to the parent molecular moiety through an amino linkage (xe2x80x94NHxe2x80x94), where R77 is an alkyl group. Preferred groups R77 are loweralkyl groups.
The term xe2x80x9calkynylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term xe2x80x9clower alkynylxe2x80x9d refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9calkynylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term xe2x80x9clower alkynylenexe2x80x9d refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1Cxe2x80x94, and the like.
The term xe2x80x9caminoalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended an amino (xe2x80x94NH2) group.
The term xe2x80x9carylxe2x80x9d as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (xe2x95x90O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, NH2C(xe2x95x90O)xe2x80x94, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted (heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and xe2x80x94SO3H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
The term xe2x80x9c(aryl)alkenylxe2x80x9d refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.
The term xe2x80x9c(aryl)alkylxe2x80x9d refers to a loweralkyl group having appended thereto an aryl group. Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94Oxe2x80x94R76 where R76 is an arylalkyl group.
The term xe2x80x9c(aryl)alkynylxe2x80x9d refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94Oxe2x80x94R72, where R72 is an aryl group.
The term xe2x80x9ccarbamoylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94NH2.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein, refers to the group having the formula, xe2x80x94R64xe2x80x94COOH, where R64 is a lower alkylene group.
The term xe2x80x9ccyanoalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a cyano group (xe2x80x94CN).
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term xe2x80x9c(cycloalkenyl)alkenylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
The term xe2x80x9c(cycloalkenyl)alkylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
The term xe2x80x9c(cycloalkenyl)alkynylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a n aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term xe2x80x9c(cycloalkyl)alkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term xe2x80x9c(cycloalkyl)alkenylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkenyl radical . Representative examples of (cycloalkyl)-alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.
The term xe2x80x9c(cycloalkyl)alkynylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl) alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94N(R90)2 wherein each R90 is independently a lower alkyl group. Representative examples of dialkylamino include dimethylamino, diethylamino, N-methyl-N-isopropylamino and the like.
The term xe2x80x9cdialkylaminocarbonylalkylxe2x80x9d as used herein refers to a xe2x80x94C(O)xe2x80x94N(R90)2 group (wherein each R90 is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonylalkyl include dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, N-methyl-N-ethylaminocarbonylethyl and the like.
The term xe2x80x9cdialkylaminocarbonyloxyalkylxe2x80x9d as used herein refers to a xe2x80x94Oxe2x80x94C(O)xe2x80x94N(R90)2 group (wherein each R90 is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonyloxyalkyl include dimethylaminocarbonyloxymethyl, diethylaminocarbonyloxymethyl, N-methyl-N-ethylaminocarbonyloxyethyl and the like.
The term xe2x80x9cenantiomerically enrichedxe2x80x9d as used herein refers to a compound which comprises unequal amounts of the enantiomers of an enantiomeric pair. In other words, an enantiomerically enriched compound comprises more than 50% of one enantiomer of an enantiomeric pair and less than 50% of the other enantiomer of the enantiomeric pair. Preferably, a compound that is enantiomerically enriched comprises predominantly one enantiomer of an enantiomeric pair. Preferably, an enantiomerically enriched compound comprises greater than 80% of one enantiomer of an enantiomeric pair and less than 20% of the other enantiomer of the enantiomeric pair. More preferably, an enantiomerically enriched compound comprises greater than 90% of one enantiomer of an enantiomeric pair and less than 10% of the other enantiomer of the enantiomeric pair. Even more preferably, an enantiomerically enriched compound comprises greater than 95% of one enantiomer of an enantiomeric pair and less than 5% of the other enantiomer of the enantiomeric pair. Even more highly preferably, an enantiomerically enriched compound comprises greater than 97% of one enantiomer of an enantiomeric pair and less than 3% of the other enantiomer of the enantiomeric pair. Yet even more highly preferably, an enantiomerically enriched compound comprises greater than 98% of one enantiomer of an enantiomeric pair and less than 2% of the other enantiomer of the enantiomeric pair. Most preferably, an enantiomerically enriched compound comprises greater than 99% of one enantiomer of an enantiomeric pair and less than 1% of the other enantiomer of the enantiomeric pair.
The term xe2x80x9chaloxe2x80x9d as used herein refers to F, Cl, Br or I.
The term xe2x80x9chaloalkenylxe2x80x9d as used herein refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2-difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene and the like.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
The term xe2x80x9chaloalkylxe2x80x9d as used herein, refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, pentafluoroethyl and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl,1,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula 
where X* is xe2x80x94CH2 or xe2x80x94Oxe2x80x94 and Y* is xe2x80x94C(O)xe2x80x94 or [xe2x80x94C(R92)2xe2x80x94]y where R92 is hydrogen or C1-C4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.
The term xe2x80x9c(heterocyclic)alkenylxe2x80x9d as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
The term xe2x80x9c(heterocyclic)alkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94OR68, where R68 is a (heterocyclic)alkyl group.
The term xe2x80x9c(heterocyclic)alkylxe2x80x9d as used herein refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
The term xe2x80x9c(heterocyclic)alkynylxe2x80x9d as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
The term xe2x80x9c(heterocyclic)carbonylalkylxe2x80x9d as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyl group. Representative examples of (heterocyclic)carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
The term xe2x80x9c(heterocyclic)carbonyloxyalkylxe2x80x9d as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyloxy group (i.e., xe2x80x94C(O)xe2x80x94Oxe2x80x94). Representative examples of (heterocyclic)carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
The term xe2x80x9c(heterocyclic)oxyxe2x80x9d as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (xe2x80x94Oxe2x80x94).
The term xe2x80x9chydroxy protecting groupxe2x80x9d, xe2x80x9chydroxyl protecting groupxe2x80x9d or xe2x80x9cxe2x80x94OH protecting groupxe2x80x9d as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is incorporated herein by reference. Such hydroxy protecting groups include:
methyl ether;
substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
benzyl ether;
substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94R65xe2x80x94OH, where R65 is an alkylene group
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-Sxe2x80x94), triphenylmethylsulfenyl (trityl-Sxe2x80x94) and the like; sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)xe2x80x94), t-butylsulfinyl (t-Bu-S(O)xe2x80x94) and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxy-carbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxy-carbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycar-bonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like; p-methoxyphenyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycar bonyl (Cbz).
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to groups having the formula xe2x80x94SR98 wherein R98 is an alkyl group. Preferred groups R98 are loweralkyl groups.
The term xe2x80x9cthio-substituted alkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a thiol group (xe2x80x94SH).
As used herein, the terms xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By xe2x80x9csubstantially freexe2x80x9d is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
In addition, solvates and hydrates of the compounds of Formula Ia, Ib, IIa, IIb, IIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb , XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb are meant to be included in this invention.
When any variable (for example R1, R2, R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
This invention is intended to encompass compounds having Formula Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
Compounds of the invention can be prepared according to the methods described in Schemes 1-11 as shown below.
Throughout the schemes, methods will be illustrated wherein R1 is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R1 substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
In adddition, throughout the schemes, methods will be illustrated wherein R4, R6, R7, R8, R9 and R10 are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, unless otherwise noted, throughout the schemes methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated wherein X is xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94. It will be understood by those skilled in the art that other X groups can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
Compounds of the invention can be prepared according to the procedure described in Scheme 1. N-protected amino acid 1 (P1 is an N-protecting group, for example, t-butoxycarbonyl or the like) can be prepared by N-protection of amino acid ((xc2x1)-(2R,3S)-2-Amino-bicyclo[2.2.1 ]hept-5-ene-3-carboxylic acid; Stajer, G. et al. Tetrahedron, 40, 2385 (1984)). Formation of an anhydride derivative of the acid (for example, by reaction with ethyl chloroformate or the like), followed by reduction (for example, with sodium borohydride or the like) provides alcohol 2. The alcohol group is oxidized (for example, by Swern oxidation or the like) to provide aldehyde 3. Reductive amination of the aldehyde (for example with benzyl amine and Na(AcO)3BH or the like) provides N-protected amine 4 (P2 is an N-protecting group, such as benzyl and the like). A second N-protecting group can be introduced to give 5 (P3 is an N-protecting group, for example, benzyloxycarbonyl or the like). Optionally, the mono-protected amino group can be alkylated (for example, by reaction with a non-nucleophilic base and an alkyl halide). The bicyclic ring is oxidatively cleaved (for example, with RuO2 and NaIO4 or the like) to give a diacid which is esterified to give diester 6 (P4 is a carboxylic acid protecting group, for example, loweralkyl, such as methyl, ethyl or the like). The N-protecting groups P2 and P3 are selectively removed (for example, by hydrogenation or the like) to provide amine 7. Amine 7 can be further functionalized to complete the introduction of the R2xe2x80x94Xxe2x80x94 substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like) to give 8. Removal of the acid protecting groups P4 (for example, by base hydrolysis) provides diacid 9. Diacid 9 can be monoprotected (for example, by treatment with acetic anhydride, followed by methanol and triethylamine) and chromatographic separation to give 10 (P5 is a carboxylic acid protecting group, for example, loweralkyl or the like). The acid group of 10 can also be transformed to a variety of substituents Y of the compounds of the invention using methods known to those skilled in the art to give 11, followed by N-deprotection, to give compounds of the invention 12.
As shown in Scheme 2, substituents R3 can be introduced via reaction of aldehyde 3 with a Grignard reagent (for example, R3MgBr or the like) to give alcohol 13. Oxidation of alcohol 13 (for example, Swern oxidation or the like) provides ketone 14. Reductive amination of ketone 14 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 15. Amine 15 can be further functionalized to complete introduction of the R2xe2x80x94Xxe2x80x94 substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 16a. The other diastereomer (16b) can also be isolated and further transformed according to the scheme.
Oxidation of 16a and esterification gives 17 (in a manner analogous to that disclosed in Scheme 1). Also similar to Scheme 1, the diacid resulting from hydrolysis of diester 17 can be selectively protected to give give 18, which can then be transformed to compounds of the invention 19.
As shown in Scheme 3, diol 20 is selectively diprotected (Culbertson, et al., Journal of the American Chemical Society 82, 2541-2547 (1960)) by reaction with one equivalent of a hydroxy protecting agent, followed by reaction with a second hydroxy protecting agent, to give 21 (P6 is a hydroxy protecting group, for example, acetyl or the like and P7 is a hydroxy protecting group, for example, benzyl or the like). Oxidation and esterification provide 22. Removal of protecting group P7, followed by transformation of the hydroxy group to an amine, which is then N-protected, provides 24. Transformation of 24 in a manner analogous to the transformation of 2 to 11 or 12 in Scheme 1 provides compounds of the invention 27 or 28.
As shown in Scheme 4, alcohol 31 can be transformed to compounds of the invention 38 in a manner analogous to the transformation of 13 to 19 in Scheme 2.
As shown in Scheme 5, aldehyde 39 can be reacted with a Grignard reagent to introduce substituent R3 to give 40. Oxidation (for example, by Swern oxidation or the like) provides 41a, which can be epimerized (for example, with sodium methoxide or the like) and 41b can be obtained by chromatography. Ketone 41 b can be transformed to compounds of the invention 47 in a manner analogous to the transformation of 14 to 19 in Scheme 2.
As shown in Scheme 6, olefin 48 (P8 is a hydroxy protecting group) is converted to alcohol 48a (for example, by reaction with borane dimethylsulfide complex and hydrogen peroxide or the like). Oxidation of the alcohol to a carboxylic acid, followed by esterification with a carboxylic acid protecting group P9 and deprotection of the diol, provides 49. Selective protection of the primary alcohol with a hydroxy protecting group P10 gives 50. Oxidation of 50 (for example, Swern oxidation or the like) provides ketone 51. Reductive amination of ketone 51 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 52. Amine 52 can be further functionalized to complete the introduction of the R2xe2x80x94Xxe2x80x94 substituent (for example, by reaction with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 53a. The other diastereomeric amide (53b) can also be isolated and further functionalized according to this scheme.
Selective removal of the P8 hydroxy protecting group in 53a provides alcohol 54. Oxidation of the alcohol to an aldehyde (for example, Swern oxidation or the like) provides 55. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 55 (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or Ixe2x88x92Ph3P+CH2CH3/KOtBu, or the like) provides 56 wherein Y is an olefinic substituent. Removal of the P10 hydroxy protecting group gives alcohol 57.
The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the alcohol of 57 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 58. Aldehyde 58 can be reacted with Grignard reagents (R14MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R14Li or the like) to provide 59 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 59a and the other isomer 59b. Isomer 59a or the mixture of isomers 59 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 62. Reduction of ketone 62 (for example, with sodium borohydride in ethanol or the like) provides alcohol 59b as the major isomer, which can be isolated by chromatography. Ester hydrolysis provides compounds of the invention 63a or 63b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 59a or 59b provides ethers 60a or 60b, respectively. Ester hydrolysis provides compounds of the invention 61a or 61b, respectively, wherein Y is an olefinic substituent.
As shown in Scheme 7, reaction of ketone 62 with with Grignard reagents (R37aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R37aLi or the like) provides alcohols 64a and 64b as a mixture of alcohol diastereomers which can be separated chromatographically. Ester hydrolysis provides compounds of the invention 65a or 65b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 64a or 64b provides ethers 66a or 66b, respectively. Ester hydrolysis provides compounds of the invention 67a or 67b, respectively, wherein Y is an olefinic substituent.
Scheme 8 shows the preparation of precursor 74 for compounds of the invention which are substituted tetrahydrofurans. Alcohol 68 is oxidized to a ketone (for example, by Swern oxidation or the like), followed by oxidation of the olefin to a diol (for example, by treatment with OsO4 and N-methylmorpholine N-oxide or the like) to give 69. Diol 69 is protected as the acetonide 70. Oxidation of 70 (for example, with MCPBA or the like) provides lactone 71. lodination via the enolate of 71 provides 72. Reaction of 72 with potassium carbonate and methanol provides ester 73. Reduction of the ester provides aldehyde 74. The aldehyde provides a functional group via which substituents R3 and R2xe2x80x94Xxe2x80x94 can be introduced. Deprotection of the diol and oxidation of the diol provides functional groups via which substituents Y and R1 can be introduced.
Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
Scheme 9 illustrates a method for preparing enantiomerically enriched compounds of the invention having the preferred absolute stereochemistry. Cyclopentene 75 (wherein P4is a carboxylic acid protecting group, for example, loweralkyl, such as methyl, ethyl, t-butyl or the like) is reacted with 78 in the presence of phenyl isocyanate and triethylamine in an inert solvent, for example, benzene or the like, to provide 79. Hydrogenation of 79 (for example, by reaction with hydrochloric acid, PtO2 and H2 in methanol or the like), followed by reaction of the resulting amine with an acylating agent such as acetic anhydrige or the like or by other acylation methods gives 80. Removal of protecting group P4, for example, with sodium hydroxide in water or the like method, and deprotection of any protected functional groups in R3 provides 81. Esters or prodrugs of 81 can be prepared by methods known in the art.
Dehydroxylation of 81, for example, by reaction with 1,1xe2x80x2-thiocarbonyldiimidazole, followed by reaction with tributyltin hydride and AIDN, or a like dehydroxylation method, provides 82. Removal of protecting group P4, for example, with sodium hydroxide in water or the like method, and deprotection of any protected functional groups in R3 provides 83. Esters or prodrugs of 83 can be prepared by methods known in the art.
In a similar manner, reaction of 75 with preferred nitro compound 85 provides 80a, which can be transformed according to the methods described above to provide 81 or 83 wherein R3 is the preferred substituent comprised in 85.
Scheme 10 illustrates a method for the preparation of enantiomerically enriched compounds of the invention wherein Y is an amine or an amine-based substituent. Cyclopentene 84 (wherein P4 is a carboxylic acid protecting group, for example, loweralkyl, such as methyl, ethyl, t-butyl or the like and P11 is an N-protecting group, for example, t-butyloxycarbonyl or the like) is reacted with 85 (wherein R37a, R37c and R14 are as defined most broadly herein and wherein, preferably, R37a is loweralkyl or loweralkenyl, R37c is hydrogen, C1-C3 loweralkyl or allyl and R14 is loweralkyl, loweralkenyl or alkoxy-substituted loweralkyl) in the presence of phenyl isocyanate and triethylamine in an inert solvent, for example, benzene, or the like, to provide 86. Hydrogenation of 86 (for example, by reaction with hydrochloric acid, PtO2 and H2 in methanol or the like), followed by reaction of the resulting amine with an acylating agent such as acetic anhydride or the like or by other acylation methods gives 87. Removal of protecting group P11, for example by reaction with trifluoroacetic acid in methylene chloride or the like method, and removal of protecting group P4, for example, with sodium hydroxide in water or the like method provides 88. For example, in those cases where R37c is hdyrogen, the hydroxy group may be protected throughout the process of Scheme 10. Esters or prodrugs of 88 can be prepared by methods known in the art.
Removal of protecting group P11 in 87, for example by reaction with trifluoroacetic acid in methylene chloride or the like method, followed by reaction of the amine with N,Nxe2x80x2-bis(tert-butoxycarbonyl)-thiourea, triethylamine and mercury(II) chloride in an inert solvent such as DMF or the like, or like method, followed by deprotection of the guanidino group, for example, with trifluoroacetic acid in methylene chloride or like method, and removal of protecting group P4, for example, with sodium hydroxide in water or the like method provides guanidino compound 89. Esters or prodrugs of 89 can be prepared by methods known in the art.
Dehydroxylation of 87, for example, by reaction with 1,1xe2x80x2-thiocarbonyldiimidazole, followed by reaction with tributyltin hydride and AIDN, or a like dehydroxylation method, provides 90, which can be converted to 91 or 92 as described herein. Esters or prodrugs of 91 and 92 can be prepared by methods known in the art.
Scheme 11 illustrates a method for preparing preferred nitro compounds 85. Allylic alcohol 93 (wherein R14a and the carbon to which it is bonded, when taken together, will become substituent R14) is asymmetrically epoxidized, for example, by Sharpless epoxidation with t-butyl hydroperoxide, (xe2x88x92)-dimethyl D-tartrate and titanium tetraisopropoxide or the like in an inert solvent such as dichloromethane and the like and the alcohol is protected (for example, P12 is benzoate or the like) to give 94. Epoxide 94 is reduced, for example, with lithium aluminum hydride or the like in an inert solvent such as THF or the like, followed by protection of the primary alcohol of 95 (for example, P13 is benzyl or the like) to give 96. Where R37c is other than hydrogen, 96 is reacted with a non-nucleophilic strong base, for example, sodium bis(trimethylsilyl)amide or the like, and R37cxe2x80x94X wherein X is a halide or other leaving group in an inert solvent such as THF or the like to provide 97. Where R37c is hydrogen, the hydroxy group is protected. Protecting group P13 is removed, preferably, selectively if any other hydroxy protecting groups are present in the compound, for example, by hydrogenation when it is a benzyl group, and the resulting alcohol is oxidized to an aldehyde, for example, with pyridinium chlorochromate or the like to give aldehyde 98. Reaction of 98 with hydroxylamine gives oxime 99. Oxidation of the oxime 99, for example, with trifluoroacetic anhydride and hydrogen peroxide in acetonitrile or a like method, provides nitro compound 85. 
The other compounds of the invention can be readily prepared from the compounds available through commercial sources, in the chemical lliterature or as described herein using techniques well known in the chemical literature. The procedures required are well known and can be readily practiced by those having ordinary skill in the art.
The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA); Alfa Aesar (Ward Hill, Mass. 01835-9953); Eastman Chemical Company (Rochester, N.Y. 14652-3512); Lancaster Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 08901); Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.